Essential fatty acids (EFAs), necessary for growth, development, and a variety of biological functions, must be provided by the diet. Historically, polyunsaturated fatty acids (PUFA) alpha linolenic acid (ALA, n-3 PUFA) and linoleic acid (LA, n-6 PUFA) have been considered the two essential fatty acids. However, recent reports have shown that the downstream metabolic products of ALA and LA, docosahexaenoic acid (DHA) and arachidonic acid (ARA), respectively, are sufficient to sustain growth, development and reproductive function (Le et al., Prostaglandins, leukotrienes, and essential fatty acids. 2009; 81(2-3):165-170; Ling et al., Metabolism: clinical and experimental, 2012; 61(10):1443-1451; and Nehra et al., Aging cell. 2012; 11(6):1046-1054).
For individuals dependent on parenteral nutrition (PN), EFAs must be provided intravenously as a lipid emulsion. Commercially available lipid formulations in the United States have been exclusively soybean oil-based and contain high levels of LA and lower levels of ALA. Soybean oil-based lipid emulsions are implicated in the development of parenteral nutrition-associated liver disease (PNALD), a progressive and often lethal complication affecting up to 74% of patients dependent on long-term PN (Colomb et al., JPEN Journal of parenteral and enteral nutrition. 2000; 24(6):345-350; Kurvinen et al., Journal of pediatric gastroenterology and nutrition. 2012; 54(6):803-811; Merritt. Journal of pediatric gastroenterology and nutrition. 1986; 5(1):9-22; Squires et al. The Journal of pediatrics. 2012; 161(4):723-728 e722).
The reduction of the total lipid dose of soybean-based lipid emulsions from 2-3 g/kg/day to 1 g/kg/day has been discussed in some previous reports to decrease the risk of development of PNALD (Cober et al. The Journal of pediatrics. 2012; 160(3):421-427; Sanchez et al. Journal of pediatric surgery. 2013; 48(3):573-578). However, these reports were not supported by Nehra et al., who demonstrated that a lipid-restrictive practice does not prevent cholestasis or PNALD (JPEN Journal of parenteral and enteral nutrition. 2013; 37(4):498-505). Alternative lipid sources have been previously discussed as another potential strategy to prevent liver disease in PN-dependent individuals. For example, a fish oil-based lipid emulsion, provided at 1 g/kg/day, has been discussed to reverse the progression toward liver failure in patients with PNALD (Calkins et al., JPEN Journal of parenteral and enteral nutrition. 2013; 38(6): 682-692; Premkumar et al. The Journal of pediatrics. 2013; 162(4):793-798 e791; and Puder et al. Annals of surgery. 2009; 250(3):395-402). Additionally, fish oil has been previously discussed to prevent essential fatty acid deficiency and enhance growth (Strijbosch et al., Metabolism, 2008, 57: 698-707). However, PN formulations provided with low doses of lipids necessitate higher calories from carbohydrates (e.g., dextrose) in order to meet the daily caloric needs of the PN-dependent individual, a consideration that is especially important in developing infants and children. PN formulations high in dextrose predispose patients to hyperglycemia and increased central venous catheter infections, hepatic steatosis, and glycosuria, complications that can lead to significant morbidity and mortality in an already-fragile population (Guglielmi et al. The journal of vascular access. 2012, 13(4):490-497; Pironi et al. Gut. 2011, 60(1):17-25; Sanders et al. American journal of surgery. 1976; 132(2):214-220).
Recently, non-essential fatty acids, so called “EFA-free” lipids, have been discussed to be utilized as additives to lipid emulsions in order to augment the total fat calories provided and decrease the requirement for additional dextrose in PN. Ling et al. discussed the metabolic effects of combinations of EFAs with hydrogenated coconut oil (HCO), an EFA-free lipid source and reported that rats fed a diet with HCO as the sole source of calories showing lower inflammatory response after an endotoxin challenge, as measured by serum IL-6 and C-reactive protein, when compared to rats fed HCO supplemented with DHA and ARA (Metabolism: clinical and experimental, 2012; 61(3):395-406). Cook et al reported a decreased systemic inflammatory response in states of essential fatty acid deficiency in rats (The Journal of clinical investigation. 1980; 65(1):227-230).
Medium-chain triglycerides (MCT) oil has been previously discussed to prevent alcohol-induced liver injury in animal models (Kono et al., American journal of physiology. Gastrointestinal and liver physiology. 2000, 278(3):G467-476; Nanji et al., The Journal of pharmacology and experimental therapeutics. 2001, 299(2):638-644; Ronis et al., The Journal of nutrition. 2004; 134(4):904-912). Other previous reports have discussed that dietary supplementation of MCT can reduce the degree of endotoxin-induced intestinal and hepatic injury in rats (Kono et al., American journal of physiology. Gastrointestinal and liver physiology. 2004, 286(6):G1081-1089; and Kono et al., Annals of surgery. 2003; 237(2):246-255). MCT were also discussed for several potential therapeutic applications including inflammatory bowel disease and, in combination with a ketogenic diet, neurological conditions such as Alzheimer's disease and epilepsy (Chang et al., Neuropharmacology. 2013; 69:105-114; Kono et al., Translational research: the journal of laboratory and clinical medicine. 2010; 156(5):282-291; Reger et al. Neurobiology of aging. 2004; 25(3):311-314).
In 2012, the American Society of Parenteral and Enteral Nutrition discussed alternatives oil-based fat emulsions other than soybean-oil based fat emulsion and suggested further research is required to identify optimum intravenous fat emulsions for specific patient populations in a compromised state. Vanek et al., Nutrition in clinical practice: Official publication of the American Society for Parenteral and Enteral Nutrition, 2012, 27:150-192. Accordingly, there is a need for development of an optimized lipid formulation, which provides sufficient EFAs to sustain growth and development, while modifying the intensity of inflammation. These lipid formulations should be of high value to the PN-dependent population.